Astrocyte-derived MFG-E8 facilitates microglial synapse elimination in Alzheimer's disease mouse models

Sokolova, D.; Addington Ghansah, S.; Puletti, F.; Georgiades, T.; De Schepper, S.; Zheng, Y.; Crowley, G.; Wu, L.; Rueda-Carrasco, J.; Koutsiouroumpa, A.; Muckett, P.; Freeman, O. J.; Khakh, B. S.; Hong, S.

doi:10.1101/2024.08.31.606944

bioRxiv · 10.1101/2024.08.31.606944

Astrocyte-derived MFG-E8 facilitates microglial synapse elimination in Alzheimer's disease mouse models

Sokolova, D.·Addington Ghansah, S.·Puletti, F.·Georgiades, T.·De Schepper, S.·Zheng, Y.·Crowley, G.·Wu, L.·Rueda-Carrasco, J.·Koutsiouroumpa, A.·Muckett, P.·Freeman, O. J.·Khakh, B. S.·Hong, S.

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Abstract

Region-specific synapse loss is an early pathological hallmark in Alzheimers disease (AD). Emerging data in mice and humans highlight microglia, the brain-resident macrophages, as cellular mediators of synapse loss; however, the upstream modulators of microglia-synapse engulfment remain elusive. Here, we report a distinct subset of astrocytes, which are glial cells essential for maintaining synapse homeostasis, appearing in a region-specific manner with age and amyloidosis at onset of synapse loss. These astrocytes are distinguished by their peri-synaptic processes which are bulbous in morphology, contain accumulated p62-immunoreactive bodies, and have reduced territorial domains, resulting in a decrease of astrocyte-synapse coverage. Using integrated in vitro and in vivo approaches, we show that astrocytes upregulate and secrete phagocytic modulator, milk fat globule-EGF factor 8 (MFG-E8), which is sufficient and necessary for promoting microglia-synapse engulfment in their local milieu. Finally, we show that knocking down Mfge8 specifically from astrocytes using a viral CRISPR-saCas9 system prevents microglia-synapse engulfment and ameliorates synapse loss in two independent amyloidosis mouse models of AD. Altogether, our findings highlight astrocyte-microglia crosstalk in determining synapse fate in amyloid models and nominate astrocytic MFGE8 as a potential target to ameliorate synapse loss during the earliest stages of AD.

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Sokolova, D., Addington Ghansah, S., Puletti, F., Georgiades, T., De Schepper, S., Zheng, Y., Crowley, G., Wu, L., Rueda-Carrasco, J., Koutsiouroumpa, A., Muckett, P., Freeman, O. J., Khakh, B. S., Hong, S.. 2024-09-01. Astrocyte-derived MFG-E8 facilitates microglial synapse elimination in Alzheimer's disease mouse models. https://doi.org/10.1101/2024.08.31.606944

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